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【结 构 式】 
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【分子编号】58916 【品名】tert-butyl 4-[(4-{3-[(4R)-4-methyl-2,5-dioxoimidazolidinyl]propoxy}phenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylate 【CA登记号】 |
【 分 子 式 】C23H32N2O8S 【 分 子 量 】496.58176 【元素组成】C 55.63% H 6.5% N 5.64% O 25.78% S 6.46% |
合成路线1
该中间体在本合成路线中的序号：(XI)Tetrahydropyran-4-carboxylic acid tert-butyl ester (I) is treated with 4-fluorophenyl disulfide (II) in the presence of LDA to produce sulfide (III), which is further oxidized to the corresponding sulfone (IV) utilizing m-chloroperbenzoic acid. Displacement of the aryl fluoride (IV) with the sodium alkoxide of 3-(dibenzylamino)-1-propanol (V) affords the amino ether (VI). Debenzylation of (VI) by hydrogenation in the presence of Pd(OH)2/C gives the primary amine (VII). This is coupled with N-Boc-D-alanine (VIII) employing EDC to provide amide (IX). Cyclization of (IX) in the presence of DMAP, NMM and Boc2O leads to the N-protected hydantoin (X). The N-Boc group of (X) is then selectively removed by HCl in dioxane to furnish (XI).
| 【1】 Becker, D.P.; Villamil, C.; Barta, T.E.; et al.; Design and synthesis of potent and selective 4,4-disubstituted alpha-sulphones hydroxamates as MMP inhibitors. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 309. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 58908 | tert-butyl tetrahydro-2H-pyran-4-carboxylate | C10H18O3 | 详情 | 详情 | |
| (II) | 52287 | bis(4-fluorophenyl) disulfide; 1-fluoro-4-[(4-fluorophenyl)disulfanyl]benzene | C12H8F2S2 | 详情 | 详情 | |
| (III) | 58809 | allyl 3-({(tert-butoxycarbonyl)[4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinyl]amino}methyl)-5-methoxyphenylcarbamate | C33H50N4O8Si | 详情 | 详情 | |
| (IV) | 58910 | tert-butyl 4-[(4-fluorophenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylate | C16H21FO5S | 详情 | 详情 | |
| (V) | 58911 | 3-(Dibenzylamino)-1-propanol | C17H21NO | 详情 | 详情 | |
| (VI) | 58912 | tert-butyl 4-({4-[3-(dibenzylamino)propoxy]phenyl}sulfonyl)tetrahydro-2H-pyran-4-carboxylate | C33H41NO6S | 详情 | 详情 | |
| (VII) | 58913 | tert-butyl 4-{[4-(3-aminopropoxy)phenyl]sulfonyl}tetrahydro-2H-pyran-4-carboxylate | C19H29NO6S | 详情 | 详情 | |
| (VIII) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (IX) | 58914 | tert-butyl 4-({4-[3-({(2R)-2-[(tert-butoxycarbonyl)amino]propanoyl}amino)propoxy]phenyl}sulfonyl)tetrahydro-2H-pyran-4-carboxylate | C27H42N2O9S | 详情 | 详情 | |
| (X) | 58915 | tert-butyl (5R)-3-[3-(4-{[4-(tert-butoxycarbonyl)tetrahydro-2H-pyran-4-yl]sulfonyl}phenoxy)propyl]-5-methyl-2,4-dioxo-1-imidazolidinecarboxylate | C28H40N2O10S | 详情 | 详情 | |
| (XI) | 58916 | tert-butyl 4-[(4-{3-[(4R)-4-methyl-2,5-dioxoimidazolidinyl]propoxy}phenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylate | C23H32N2O8S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)N-Arylation of hydantoin (XI) with phenylboronic acid in the presence of cupric acetate gives rise to the N-phenyl hydantoin (XII). Subsequent hydrolysis of the tert-butyl ester with trifluoroacetic acid in CH2Cl2 affords acid (XIII). This is then coupled with O-(tetrahydropyranyl)-hydroxylamine, yielding the tetrahydropyranyl-protected hydroxamic acid (XIV). Finally, removal of the tetrahydropyranyl protecting group of (XIV) under acidic conditions provides the title compound.
| 【1】 Becker, D.P.; Villamil, C.; Barta, T.E.; et al.; Design and synthesis of potent and selective 4,4-disubstituted alpha-sulphones hydroxamates as MMP inhibitors. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 309. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 58916 | tert-butyl 4-[(4-{3-[(4R)-4-methyl-2,5-dioxoimidazolidinyl]propoxy}phenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylate | C23H32N2O8S | 详情 | 详情 | |
| (XII) | 58917 | tert-butyl 4-[(4-{3-[(4R)-4-methyl-2,5-dioxo-3-phenylimidazolidinyl]propoxy}phenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylate | C29H36N2O8S | 详情 | 详情 | |
| (XIII) | 58918 | 4-[(4-{3-[(4R)-4-methyl-2,5-dioxo-3-phenylimidazolidinyl]propoxy}phenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylic acid | C25H28N2O8S | 详情 | 详情 | |
| (XIV) | 58919 | 4-[(4-{3-[(4R)-4-methyl-2,5-dioxo-3-phenylimidazolidinyl]propoxy}phenyl)sulfonyl]-N-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-4-carboxamide | C30H37N3O9S | 详情 | 详情 |